Delving into the Latest Updates on PNU-96391 with Synapse

This is a randomised, placebo-controlled, parallel-group trial comparing OSU6162 at flexible dosage with placebo as add-on to treatment with an SSRI/SNRI in patients with depression that have not responded to treatment with an SSRI/SNRI per se for at least 6 weeks. The study will last for 6 weeks, after which those not having responded will leave the trial and those having responded will be offered to continue treatment without unblinding for another 4 weeks. Optional Substudy 1 and 2: Baseline and treatment-associated change in reward-related striatal activity per fMRI-assessment. (Substudy 1).
Brain signal variability per fMRI-assessment. (Substudy 1). Probabilistic Reward Task (PRT). (Substudy 2).
While assessment of the efficacy and safety of OSU6162 is the main objective of this study, possible differences between the two treatment groups with respect to a number of biomarkers in serum will also be explored.
Multicenter trial: Multiple sites four Gothenburg, Lund, Stockholm and Uppsala.

Start Date21 Apr 2022

Sponsor / Collaborator

Arvid Carlsson Research AB

NCT05296356

/ RecruitingPhase 2

OSU6162 in Bipolar Depression: An Open-label, Flexible Dose Study (OBID)

An explorative, open label, single armed, flexible dose, single center, phase IIa study of 8 weeks, initiated in subjects with bipolar depression. The study will consist of 9 visits and 1 safety visit.
Subjects with a primary diagnosis of bipolar disorder (type 1 or 2) currently in an acute depressive phase (i.e. bipolar depression) and being on stable medication with at least one mood stabilizer.

Start Date25 Oct 2021

Sponsor / Collaborator

University of Gothenburg

[+1]

NCT03209830

/ CompletedPhase 2IIT

OSU6162 in the Treatment of Fatigue and Other Neuropsychological Sequelae After Aneurysmal Subarachnoid Hemorrhage - A Double-blind, Randomised, Placebo-controlled Study

Many people who have undergone subarachnoid hemorrhage from an aneurysm (an artery of a vein in the brain) struggle with a pronounced fatigue as well as a number of other sequelae such as impaired concentration, memory deficits and emotional problems. Exhaustion is often permanent and can lead to a significant worsening of quality of life and be the cause of disability. This condition does not only have major consequences for the individual who is affected, but also for their families and for society. So far no effective treatment for fatigue has been found. The drug OSU6162 has shown a beneficial effect on fatigue and other impairments after stroke and after traumatic brain injury. There is good reason to believe that OSU6162 can also improve fatigue and other impairments after aneurysm bleeding and thus increase the chance of returning to the level of daily function they had before the bleeding. The study is double blinded and measures the effect of OSU6162 and placebo on fatigue and neuropsychological function.

Start Date05 Sep 2017

Sponsor / Collaborator

Oslo universitetssykehus HF

[+2]

100 Clinical Results associated with PNU-96391

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100 Translational Medicine associated with PNU-96391

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100 Patents (Medical) associated with PNU-96391

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68

Literatures (Medical) associated with PNU-96391

01 Jan 2023·Frontiers in molecular neuroscience

Combined treatment with Sigma1R and A2AR agonists fails to inhibit cocaine self-administration despite causing strong antagonistic accumbal A2AR-D2R complex interactions: the potential role of astrocytes.

Article

Author: Zhou, Zilong ; Fuxe, Kjell ; Filip, Malgorzata ; Borroto-Escuela, Dasiel O ; Suder, Agata ; Frankowska, Malgorzata ; Romero-Fernandez, Wilber ; Wydra, Karolina ; Bartolini, Marco ; Benitez-Porres, Javier ; Lopez-Salas, Alexander

Previous studies have indicated that acute treatment with the monoamine stabilizer OSU-6162 (5 mg/kg), which has a high affinity for Sigma1R, significantly increased the density of accumbal shell D2R-Sigma1R and A2AR-D2R heteroreceptor complexes following cocaine self-administration. Ex vivo studies using the A2AR agonist CGS21680 also suggested the existence of enhanced antagonistic accumbal A2AR-D2R allosteric interactions after treatment with OSU-6162 during cocaine self-administration. However, a 3-day treatment with OSU-6162 (5 mg/kg) failed to alter the behavioral effects of cocaine self-administration. To test these results and the relevance of OSU-6162 (2.5 mg/kg) and/or A2AR (0.05 mg/kg) agonist interactions, we administered low doses of receptor agonists during cocaine self-administration and assessed their neurochemical and behavioral effects. No effects were observed on cocaine self-administration; however, marked and highly significant increases using the proximity ligation assay (PLA) were induced by the co-treatment on the density of the A2AR-D2R heterocomplexes in the nucleus accumbens shell. Significant decreases in the affinity of the D2R high- and low-affinity agonist binding sites were also observed. Thus, in low doses, the highly significant neurochemical effects observed upon cotreatment with an A2AR agonist and a Sigma1R ligand on the A2AR-D2R heterocomplexes and their enhancement of allosteric inhibition of D2R high-affinity binding are not linked to the modulation of cocaine self-administration. The explanation may be related to an increased release of ATP and adenosine from astrocytes in the nucleus accumbens shell in cocaine self-administration. This can lead to increased activation of the A1R protomer in a putative A1R-A2AR-D2R complex that modulates glutamate release in the presynaptic glutamate synapse. We hypothesized that the integration of changes in presynaptic glutamate release and postjunctional heteroreceptor complex signaling, where D2R plays a key role, result in no changes in the firing of the GABA anti-reward neurons, resulting in no reduction in cocaine self-administration in the present experiments.

01 Jan 2023·Molecular Psychiatry

Hypodopaminergic state of the nigrostriatal pathway drives compulsive alcohol use

Article

Author: Mallet, David ; Bartolomucci, Magali ; Joly, Fanny ; Chovelon, Benoit ; Vossier, Frédérique ; Carcenac, Carole ; Guicherd, Denis ; Dufourd, Thibault ; Deransart, Colin ; Boulet, Sabrina ; Carnicella, Sebastien ; Goutaudier, Raphaël

AbstractThe neurobiological mechanisms underlying compulsive alcohol use, a cardinal feature of alcohol use disorder, remain elusive. The key modulator of motivational processes, dopamine (DA), is suspected to play an important role in this pathology, but its exact role remains to be determined. Here, we found that rats expressing compulsive-like alcohol use, operationalized as punishment-resistant self-administration, showed a decrease in DA levels restricted to the dorsolateral territories of the striatum, the main output structure of the nigrostriatal DA pathway. We then causally demonstrated that chemogenetic-induced selective hypodopaminergia of this pathway resulted in compulsive-like alcohol self-administration in otherwise resilient rats, accompanied by the emergence of alcohol withdrawal-like motivational impairments (i.e., impaired motivation for a natural reinforcer). Finally, the use of the monoamine stabilizer OSU6162, previously reported to correct hypodopaminergic states, transiently decreased compulsive-like alcohol self-administration in vulnerable rats. These results suggest a potential critical role of tonic nigrostriatal hypodopaminergic states in alcohol addiction and provide new insights into our understanding of the neurobiological mechanisms underlying compulsive alcohol use.

23 Nov 2022·Journal of the American Chemical Society

Synthesis of Stereoenriched Piperidines via Chemo-Enzymatic Dearomatization of Activated Pyridines

Article

Author: Angelastro, Antonio ; Whitehead, Roger C. ; Sangster, Jack J. ; Pirvu, Lucian ; Thorpe, Thomas W. ; Gilio, Amelia K. ; Nafie, Jordan W. ; Grogan, Gideon ; Finnigan, James D. ; Charnock, Simon J. ; Marshall, James R. ; Heath, Rachel S. ; Harawa, Vanessa ; Turner, Nicholas J.

The development of efficient and sustainable methods for the synthesis of nitrogen heterocycles is an important goal for the chemical industry. In particular, substituted chiral piperidines are prominent targets due to their prevalence in medicinally relevant compounds and their precursors. A potential biocatalytic approach to the synthesis of this privileged scaffold would be the asymmetric dearomatization of readily assembled activated pyridines. However, nature is yet to yield a suitable biocatalyst specifically for this reaction. Here, by combining chemical synthesis and biocatalysis, we present a general chemo-enzymatic approach for the asymmetric dearomatization of activated pyridines for the preparation of substituted piperidines with precise stereochemistry. The key step involves a stereoselective one-pot amine oxidase/ene imine reductase cascade to convert N-substituted tetrahydropyridines to stereo-defined 3- and 3,4-substituted piperidines. This chemo-enzymatic approach has proved useful for key transformations in the syntheses of antipsychotic drugs Preclamol and OSU-6162, as well as for the preparation of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib.

100 Deals associated with PNU-96391

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder, Treatment-Resistant	Phase 2	Sweden	Arvid Carlsson Research AB	21 Apr 2022
Bipolar I disorder	Phase 2	Sweden	Arvid Carlsson Research AB	25 Oct 2021
Fatigue Syndrome, Chronic	Phase 2	-	NTG Nordic Transport Group A/S	-
Fatigue Syndrome, Chronic	Phase 2	-	Karolinska Institutet	-
Aneurysm, Intracranial Berry, 1	Preclinical	Norway	Oslo universitetssykehus HF	05 Sep 2017
Fatigue	Preclinical	Norway	Oslo universitetssykehus HF	05 Sep 2017
stroke; sequelae	Preclinical	Sweden	Arvid Carlsson Research AB	20 Mar 2017
Huntington Disease	Preclinical	United States	Pharmacia & Upjohn, Inc.	31 Dec 1999
Parkinson Disease	Preclinical	United States	-	-